Sleep deprivation disrupts vital biological processes necessary for cognitive ability and physical health, but the nature of the underlying physiological changes are largely unknown. The purpose of the present studies of sleep deprivation in rats is to delineate the pathophysiology and its mediation. Plasma total thyroid hormones decline to severely low levels in sleep- deprived rats; a metabolic complication that is associated with other signs, such as the development of hypothermia and a decrease in resistance to infection. Possible hypothalamic, pituitary, and thyroidal causes of decreased circulating T4 were evaluated. The free hormones were measured to minimize binding irregularities, and the pituitary- thyroid axis was challenged with i.v. thyrotropin-releasing hormone (TRH) to determine (1) pituitary release of thyroid-stimulating hormone (TSH) and (2) thyroidal response of free T4 (FT4) and free T3 (FT3) to the TSH increment. The results indicate that FT4 and FT3 decline in a similar manner to TT4 and TT3, ruling out changes in binding. In light of the low plasma T4, which is a potent stimulator of TSH release, unchanged basal and stimulated TSH concentrations and unchanged thyroidal responses to TSH release suggest an important alteration in regulation at the hypothalamic or pituitary level; i.e., central hypothyroxinemia. Metabolic mapping revealed sleep deprivation's effects on cerebral structures are heterogeneous and unidirectional toward decreased functional activity. The hypometabolic brain structures are concentrated in the hypothalamus, thalamus, and limbic system, whereas few regions in the rest of the brain are affected. Correspondence can be found between some of the structures with reduced cerebral metabolism and several of the peripheral signs of sleep deprivation. Sleep deprivation in rats decreases resistance to infectious disease. Ongoing research will extend a previous finding from this laboratory that sleep deprivation results in lethal systemic infections in rats without fever or marked tissue inflammatory responses, which, when viewed in the context of other findings, suggests that sleep deprivation is immunosuppressive. This research project is terminated within the intramural program, based on programmatic decisions. Collaborative endeavors between Dr. Everson and the Branch and other intramural scientists will continue upon Dr. Everson's relocation to the University of Tennessee, Memphis, College of Medicine, Department of Physiology and Biophysics.